U.S. patent application number 16/864894 was filed with the patent office on 2020-11-05 for dissolvable polymeric eye inserts and method of using same.
The applicant listed for this patent is ALCON INC.. Invention is credited to Stephen John Collins, Howard Allen Ketelson, Walter R. Laredo, Rekha Rangarajan.
Application Number | 20200345544 16/864894 |
Document ID | / |
Family ID | 1000004973715 |
Filed Date | 2020-11-05 |
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United States Patent
Application |
20200345544 |
Kind Code |
A1 |
Ketelson; Howard Allen ; et
al. |
November 5, 2020 |
DISSOLVABLE POLYMERIC EYE INSERTS AND METHOD OF USING SAME
Abstract
Polymeric eye inserts are provided that may be dissolvable when
placed in the cul-de-sac of the eye. These inserts may contain one
or more polymers as well as a softener/plasticizer so that, when
inserted into the eye, they may absorb tears, and dissolve and
slowly release lubricant into the tear film to lubricate and
protect the ocular surface for an extended duration of time.
Increased retention time on the ocular surface for longer lasting
relief may reduce dosing frequency and patient burden typically
associated with topical drop usage. These polymeric eye inserts
also may include one or more pharmaceutically active agents.
Inventors: |
Ketelson; Howard Allen;
(Dallas, TX) ; Rangarajan; Rekha; (Fort Worth,
TX) ; Laredo; Walter R.; (Fort Worth, TX) ;
Collins; Stephen John; (Fort Worth, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALCON INC. |
Fribourg |
|
CH |
|
|
Family ID: |
1000004973715 |
Appl. No.: |
16/864894 |
Filed: |
May 1, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62841901 |
May 2, 2019 |
|
|
|
62927885 |
Oct 30, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 47/36 20130101; A61K 47/14 20130101; A61K 47/22 20130101; A61F
9/0017 20130101; A61K 2121/00 20130101; A61K 9/0051 20130101 |
International
Class: |
A61F 9/00 20060101
A61F009/00; A61K 47/10 20060101 A61K047/10; A61K 47/22 20060101
A61K047/22; A61K 9/00 20060101 A61K009/00; A61K 47/36 20060101
A61K047/36; A61K 47/14 20060101 A61K047/14 |
Claims
1. A polymeric eye insert, the insert comprising: one or more
mucoadhesive polymers that are biocompatible with the ocular
surface and tear film of the eye; and wherein upon insertion of the
polymeric eye insert in the cul-de-sac of the eye, the thickness of
the tear film increases for at least 30 minutes post-insertion.
2. The polymeric eye insert of claim 1, wherein the one or more
mucoadhesive polymers are selected from the group consisting of:
hyaluronic acid or salts thereof, hydroxypropylmethylcellulose
(HPMC), methylcellulose, tamarind seed polysaccharide (TSP), guar,
hydroxypropyl guar (HP guar), scleroglucan poloxamer,
poly(galacturonic) acid, sodium alginate, pectin, xanthan gum,
xyloglucan gum, chitosan, sodium carboxymethylcellulose, polyvinyl
alcohol, polyvinyl pyrrolidine, carbomer, polyacrylic acid and
combinations thereof.
3. The polymeric eye insert of claim 1 wherein the one or more
mucoadhesive polymers are HP guar, hyaluronic acid, or sodium
hyaluronate.
4. The polymeric eye insert of claim 3, wherein the one or more
mucoadhesive polymers are present in an amount of from about 50% to
about 99% w/w, about 60% to about 95% w/w, about 70% to about 90%
w/w, or about 80% to about 90% w/w of the polymeric eye insert.
5. The polymeric eye insert of claim 3 further comprising a
plasticizer or softener.
6. The polymeric eye insert of claim 5 wherein the plasticizer or
softener is selected from the group consisting of: polyethylene
glycol (PEG), a PEG derivative, water, Vitamin E, and triethyl
citrate.
7. The polymeric eye insert of claims 5, wherein the plasticizer or
softener is present in an amount of from about 2% to about 30% w/w,
about 5% to about 25% w/w, about 5% to about 20% w/w, or about 5%
to about 15% w/w of the polymeric eye insert.
8. The polymeric eye insert of claim 6, wherein the plasticizer or
softener is PEG.
9. The polymeric eye insert of claim 1, wherein the insert is
comprised of approximately 40% HP guar, approximately 10% PVP,
approximately 40% sodium hyaluronate, and approximately 10%
PEG.
10. The polymeric eye insert of claim 1, further comprising 1-200
ppm menthol.
11. The polymer eye insert of claim 8, further comprising 20-100
ppm menthol.
12. The polymeric eye insert of claim 1, wherein the insert does
not include an additional pharmaceutically active agent.
13. The polymeric eye insert of claim 1, wherein the insert
comprises one or more pharmaceutically active agents.
14. The polymeric eye insert of claim 11, wherein the one or more
pharmaceutically active agents is selected from the group
consisting of: atropine derivatives which are not nitric oxide
donors, travoprost co-drug with nitric oxide, lubricants, steroids,
antibiotics, nonsteroidal anti-inflammatory drugs, anti-histamines,
anti-virals, anti-bacterials, vasoconstrictors, and prostaglandin
analogs.
15. The polymeric eye insert of claim 1, wherein the tear film
thickness does not return to pre-insertion thickness until
approximately two hours after insertion.
16. The polymeric eye insert of claim 1, wherein upon insertion in
the cul-de-sac of the eye, the thickness of the tear film increases
up to at least two hours post-insertion.
17. The polymeric eye insert of claim 1, wherein the insert shape
is a film, a rod, a sphere, an annulus, or an irregular shape
having a maximum size in any single dimension of 5-6 mm.
18. The polymeric eye insert of claim 17, wherein said insert has a
circular shape about 5 mm in diameter, a thickness of 50-400 .mu.m,
and a water content of 1% to 50% w/w.
19. The polymeric eye insert of claim 18, wherein said insert has a
thickness of about 150-250 .mu.m, and a water content of 30 to 50%
w/w.
20. The polymeric eye insert of claim 3, wherein said HP guar has a
weight average molecular weight of 2 to 4 million Daltons and said
sodium hyaluronate has a weight average molecular weight of 0.1 to
2 million Daltons.
21. (canceled)
22. A method of treating an ocular disorder, which comprises
applying the polymeric eye insert of claim 1 to the cul-de-sac of
the eye, wherein said ocular disorder is selected from the group
consisting of dry eye, eye redness, myopia, glaucoma, allergy, and
inflammation.
Description
FIELD OF THE DISCLOSURE
[0001] The present disclosure generally relates to polymeric eye
insert technology, and more particularly to dissolvable polymeric
eye inserts that release lubricants and drugs into the eye
(including, but not limited to the anterior and posterior segments)
for an extended duration of time compared to topical drop dosage
forms.
BACKGROUND
[0002] Many ophthalmic formulations comprise compounds that provide
lubricity and other desirable properties. When these formulations
are instilled in the eye, the properties of such compounds can
prevent undesirable problems such as bioadhesion and the formation
of friction-induced tissue damage, as well as encourage the natural
healing and restoration of previously damaged tissues.
[0003] Compliance with administration of topically applied
ophthalmic formulations such as liquids, ointments, gels, sprays is
often poor, specifically for the treatment of dry eye, allergy,
infection and slowly progressing diseases, such as glaucoma,
requiring multiple applications per day to lubricate and deliver a
drug to the eye. Exposure to topically administered aqueous
formulations is often driven by the short retention time of the
formulation on the ocular surface, which can be less than 25
minutes following instillation. Paugh et al., Optom Vis Sci. 2008
August; 85(8):725-31. Typical aqueous formulations for ocular use
may be diluted or washed from the ocular surface within minutes,
introduce variability in the usage, or result in less accurate and
precise dosages administered to the eye. Accordingly, there is a
need to reduce treatment burden and improve compliance.
[0004] Ointments and gels, which are highly viscous and usually
reside in the eye longer than a liquid can provide for more
accurate administration. However, they can also interfere with a
patient's vision and may require, at a minimum, dosing 2-3 times
per day. For these and other reasons the rate of discontinuation of
use can be very high. Swanson, M., J. Am. Optom. Assoc., 2011;
10:649-6.
[0005] Inserts, both bioerodible and non-bioerodible, are also
available and allow for less frequent administration. Pescina S et
al., Drug Dev Ind Pharm; 2017 May 7:1-8; Karthikeyan, MB et al.,
Asian J. Pharmacol; 2008; October-December 192-200. These inserts,
however, require complex and detailed preparation and can be
uncomfortable to the patient. An additional problem with
non-bioerodible inserts is that they must be removed after use.
However, with proper use and adequate patient education, inserts
can be an effective and safe treatment choice for dry eye
patients.
[0006] Hydroxypropyl cellulose ophthalmic inserts such as
LACRISERT.RTM. (Aton Pharmaceuticals Inc.) have been used for dry
eye patients. These inserts are translucent cellulose-based rods
measuring 1.27 mm in diameter and 3.5 mm in length. Each of these
inserts contains 5 mg of hydroxypropyl cellulose, with no
preservatives or other ingredients. The medication is administered
by placing a single insert into the inferior cul-de-sac of the eye
beneath the base of the tarsus. These inserts are indicated
particularly for patients who continue to have dry eye symptoms
following an adequate trial therapy with artificial tears. They
also are indicated for patients with keratoconjunctivitis sicca,
exposure keratitis, decreased corneal sensitivity, and recurrent
corneal erosions. Several studies have been performed to evaluate
the efficacy of HPC ophthalmic inserts. (Luchs, J, et al., Cornea,
2010; 29:1417-1427; Koffler B, et al., Eye Contact Lens; 2010;
36:170-176; McDonald M, et al., Trans Am Ophthalmol. Soc., 2009;
107:214-221; Wander A, and Koffler B, Ocul Surf 2009
July;7(3):154-62).
[0007] However, there also are challenges in using these types of
inserts. For example, LACRISERT.RTM. inserts tend to dissolve
slowly and can remain in the eye even after 15-20 hours. The rod is
hard and inelastic with edges due to rod-shaped design. The slow
dissolving properties coupled with the rod hardness and design may
lead to side effects including blurred vision, foreign body
sensation and/or discomfort, ocular irritation or hyperemia,
hypersensitivity, photophobia, eyelid edema, and caking or drying
of viscous material on eyelashes. The most common side effect of
these hydroxypropyl cellulose ophthalmic inserts is blurred vision
due to the long retention time of the insert. Thus, additional
approaches are needed to develop polymeric eye inserts that are
comfortable and improve patient compliance.
SUMMARY
[0008] The invention provides a polymeric eye insert, the insert
comprising: one or more mucoadhesive polymers that are
biocompatible with the ocular surface and tear film of the eye; and
wherein upon insertion of the polymeric eye insert in the
cul-de-sac of the eye, the thickness of the tear film increases for
at least 30 minutes post-insertion. The invention also provides a
method for of treating an ocular disorder, which comprises applying
the polymeric eye insert of the insert according to embodiments of
the present disclosure to the cul-de-sac of the eye.
[0009] The present invention is partly based on the finding that
problems of tending to dissolve slowly and remaining in the eye
even after 15-20 hours in using commercially available ophthalmic
inserts such as LACRISERT.RTM. inserts. The problem may be solved
through using a polymeric eye insert according to embodiments of
the present disclosure which is small enough to fit into the
cul-de-sac of the eye and be rapidly wetted so that there is little
or no irritation upon insertion and the insert is also large enough
to allow for dissolution over anywhere from approximately 30-120
minutes to allow for release of the lubricant(s) and/or
pharmaceutically active agents to occur. The insert also has a
thickness that is relatively comfortable for the user. A preferred
thickness is between 50-250 microns, and a most preferred thickness
is between 70-150 microns. The target thickness is 90 microns for
films dissolving in less than 2 hours
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] For a more complete understanding of this disclosure,
reference is now made to the following description, taken in
conjunction with the accompanying drawings, in which:
[0011] FIG. 1 depicts placement of a polymeric eye insert according
to embodiments of the present disclosure;
[0012] FIGS. 2A-2C depict tear film measurements for SYSTANE.RTM.
ULTRA eye drops pre-dose (FIG. 2A), immediately post-dose (FIG. 2B)
and 5 minutes post-dose (FIG. 2C);
[0013] FIGS. 3A-3C depict tear film measurements for GENTEAL.RTM.
gel drops pre-dose (FIG. 3A), immediately post-dose (FIG. 3B) and 5
minutes post-dose (FIG. 3C);
[0014] FIGS. 4A-4E depict tear film measurements for PROVISC.RTM.
injectable pre-dose (FIG. 4A), immediately post-dose (FIG. 4B), 5
minutes post-dose (FIG. 4C), 10 minutes post-dose (FIG. 4D) and 20
minutes post-dose (FIG. 4E);
[0015] FIGS. 5A-5I reflect tear film measurements associated with
insertion of a polymeric eye insert according to embodiments of the
present disclosure;
[0016] FIG. 6A reflects mean tear film measurements using polymeric
eye inserts according to an embodiment of the present
disclosure;
[0017] FIG. 6B reflects tear film measurements by individual animal
according to an embodiment of the present disclosure;
[0018] FIG. 6C reflects tear film measurements based on location in
the eye including the bottom of the eye, top of the eye, temporal
and nasal measurements according to an embodiment of the present
disclosure;
[0019] FIG. 7A reflects the dynamic change of tear film thickness
with respect to polymeric eye inserts according to embodiments of
the present disclosure;
[0020] FIG. 7B reflects tear film measurements by location (apex,
nasal, temporal, top, and bottom) for polymeric eye inserts
according to embodiments of the present disclosure;
[0021] FIG. 8 reflects mean GENTEAL.RTM. gel tear film measurements
for the right and left eye;
[0022] FIG. 9 reflects tear film thickness data as a function of
elapsed time post-dose; and
[0023] FIGS. 10A-10C illustrate various polymeric eye insert shapes
and characteristics according to embodiments of the present
disclosure.
[0024] FIG. 11 illustrates the results from the primary outcome
measure (comfort rating) of two embodiments (thick insert and thin
insert) according to embodiments of the present disclosure;
[0025] FIG. 12 illustrates the results from a secondary outcome
measure (visual blur) of two embodiments (thick insert and thin
insert) according to embodiments of the present disclosure;
[0026] FIG. 13 illustrates the results from the assessment of
polymeric eye insert dissolution of embodiments of the present
disclosure;
[0027] FIG. 14 illustrates the results from a secondary outcome
measure (NITBUT) of two embodiments (thick insert and thin insert)
according to the present disclosure;
[0028] FIG. 15 illustrates the results from a secondary outcome
measure (tear meniscus height) of two embodiments (thick insert and
thin insert) according to the present disclosure;
[0029] FIG. 16 illustrates results from the ocular irritation
question for two embodiments (thick insert and thin insert)
according to the present disclosure;
[0030] FIG. 17 illustrates results from the ocular dryness question
for two embodiments (thick insert and thin insert) according to the
present disclosure;
[0031] FIG. 18 illustrates results from the ocular burning/stinging
question for two embodiments (thick insert and thin insert)
according to the present disclosure;
[0032] FIG. 19 illustrates results from the ocular itching question
for two embodiments (thick insert and thin insert) according to the
present disclosure;
DETAILED DESCRIPTION
[0033] Embodiments of the present disclosure provide a polymeric
eye insert comprising an ocular lubricant containing one or more
polymers. In an embodiment of the present disclosure, a polymeric
eye insert may be comprised of hyaluronic acid, hydroxypropyl guar
(HP guar), and a plasticizer, such as polyethylene glycol (PEG);
however, other polymers and plasticizers/softeners may be used
without departing from the present disclosure, as described herein.
An insert according to embodiments of the present disclosure may be
inserted in the lower eye lid (also known as the cul-de-sac) of the
eye, and upon insertion, the insert may rapidly absorb tears and
dissolve to release the ocular lubricant into the tear film to
lubricate and protect the ocular surface for an extended duration
superior to previously known topical ophthalmic compositions.
Pharmaceutically active agents also may be incorporated into
polymeric eye inserts according to embodiments of the present
disclosure. Insertion of a polymeric eye insert according to
embodiments of the present disclosure may provide relief to the
patient from symptoms of dry eye as well as other eye
conditions.
[0034] The biomaterial for forming a polymeric eye insert according
to embodiments of the present disclosure may be comprised of one or
more polymers that are biocompatible with the ocular surface and
tear film. Polymers that may be used in polymeric eye inserts
according to embodiments of the present disclosure include, but are
not limited to, hyaluronic acid (in acid or salt form),
hydroxypropylmethylcellulose (HPMC), methylcellulose, tamarind seed
polysaccharide (TSP), Galactomannans, for examples; guar and
derivatives thereof such as hydroxypropyl guar (HP guar),
scleroglucan poloxamer, poly(galacturonic) acid, sodium alginate,
pectin, xanthan gum, xyloglucan gum, chitosan, sodium
carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidine,
carbomer, polyacrylic acid and/or combinations thereof.
[0035] The preferred biocompatible polymers are hyaluronic acid,
guar and derivatives and/or combinations thereof. Hyaluronic acid
is an unsulphated glycosaminoglycan composed of repeating
disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic
acid (GlcUA) linked together by alternating beta-1,4 and beta-1,3
glycosidic bonds. Hyaluronic acid is also known as hyaluronan,
hyaluronate, or HA. As used herein, the term hyaluronic acid also
includes salt forms of hyaluronic acid such as sodium hyaluronate.
A preferred hyaluronic acid is sodium hyaluronate. The weight
average molecular weight of the hyaluronic acid used in insert of
the present invention may vary, but is typically weight average
molecular weight of 0.1 to 2.0M Daltons. In one embodiment, the
hyaluronic acid has a weight average molecular weight of 0.5 to
1MDaltons. In another embodiment, the hyaluronic acid has a weight
average molecular weight of 1.5 to 2.0 M Daltons.
[0036] The galactomannans of the present invention may be obtained
from numerous sources. Such sources include from fenugreek gum,
guar gum, locust bean gum and tara gum. Additionally, the
galactomannans may also be obtained by classical synthetic routes
or may be obtained by chemical modification of naturally occurring
galactomannans. As used herein, the term "galactomannan" refers to
polysaccharides derived from the above natural gums or similar
natural or synthetic gums containing mannose or galactose moieties,
or both groups, as the main structural components. Preferred
galactomannans of the present invention are made up of linear
chains of (1-4)-.beta.-D-mannopyranosyl units
with.alpha.-D-galactopyranosyl units attached by (1-6) linkages.
With the preferred galactomannans, the ratio of D-galactose to
D-mannose varies, but generally will be from about 1:2 to 1:4.
Galactomannans having a D-galactose:D-mannose ratio of about 1:2
are most preferred. Additionally, other chemically modified
variations of the polysaccharides are also included in the
"galactomannan" definition. For example, hydroxyethyl,
hydroxypropyl and carboxymethylhydroxypropyl substitutions may be
made to the galactomannans of the present invention. Non-ionic
variations to the galactomannans, such as those containing alkoxy
and alkyl (C1-C6) groups are particularly preferred when a soft gel
is desired (e.g., hydroxylpropyl substitutions). Substitutions in
the non-cis hydroxyl positions are most preferred. An example of
non-ionic substitution of a galactomannan of the present invention
is hydroxypropyl guar, with a molar substitution of about 0.4.
Anionic substitutions may also be made to the galactomannans.
Anionic substitution is particularly preferred when strongly
responsive gels are desired, Preferred galactomannans of the
present invention are guar and hydroxypropyl guar. Hydroxypropyl
guar is particularly preferred. The weight average molecular weight
of the Hydroxypropyl guar in the insert of the present invention
may vary, but is typically 1 to 5M Daltons. In one embodiment, the
Hydroxypropyl guar has a weight average molecular weight of 2 to
4MDaltons. In another embodiment, the Hydroxypropyl guar has a
weight average molecular weight of 3 to 4 M Daltons.
[0037] Polymers used in inserts according to embodiments of the
present disclosure should be non-toxic and able to solubilize in
eye fluids to ensure that the insert is eventually cleared from the
eye, generally over a 60-minute time frame. It should be
appreciated that the polymer(s) selected should be mucoadhesive. It
also should be appreciated that one or more polymers may be blended
according to embodiments of the present disclosure. For example, in
an embodiment of the present disclosure, hyaluronic acid (HA) may
be blended with tamarind seed polysaccharide (TSP) because TSP has
been shown to increase residence time of HA in aggregate blends and
the blend has desired film mechanical and lubrication properties.
In other embodiments of the present disclosure, as described in
further detail below, hyaluronic acid may be combined with HP
guar.
[0038] In some embodiments, the one or more mucoadhesive polymers
are present in an amount of from about 50% to about 99% w/w, about
60% to about 95% w/w, about 70% to about 90% w/w, or about 80% to
about 90% w/w by dry weight of the polymeric eye insert. In
particular embodiments, the mucoadhesive polymers are present in an
amount of about 75%, about 80%, about 85%, about 90%, or about 95%
w/w by dry weight of the polymeric eye insert. The overall dry
weight or mass of the polymeric eye insert may be in the range of
about 1 to about 10 mg, or about 2 to about 8 mg, and in particular
embodiments may be from about 2.5 to about 5 mg.
[0039] In some embodiments of the present disclosure, a softener
and/or plasticizer may be added to the one or more polymers to
facilitate fabrication of a softer, malleable delivery system and
also provide improved comfort in insertion. A plasticizer may
soften the material to provide for desirable dissolution rates. It
should be appreciated softeners and/or plasticizers may be low or
high-molecular weight compounds, including not limited to,
polyethylene glycol (PEG) and derivatives thereof, water, Vitamin
E, and triethyl citrate.
[0040] In some embodiments, the plasticizer or softener is present
in an amount of from about 2% to about 30% w/w, about 5% to about
25% w/w, about 5% to about 20% w/w, or about 5% to about 15% w/w by
dry weight of the polymeric eye insert. In particular embodiments,
the plasticizer or softener is present in an amount of about 5%,
about 7%, about 10%, or 12%, or about 15%, w/w by dry weight of the
polymeric eye insert.
[0041] In some embodiments, the polymeric eye insert may have a
water content of about 1% to about 50% after hydration. In
particular embodiments, the polymeric eye insert may have a water
content of 30-40%.
[0042] The polymeric eye insert may be of any size or shape
suitable for administration to the eye. Exemplary shapes include
film, a rod, a sphere, or an irregular shape having a maximum size
in any single dimension of 5-6 mm. Additional exemplary shapes are
shown in FIGS. 10A-10C.
[0043] In some embodiments, the polymeric eye insert has a
thickness of about 50-400 .mu.m, about 100-300 .mu.m, about 150-250
.mu.m, or about 200 .mu.m.
[0044] In particular embodiments, the polymeric eye insert has a
thickness of about 150-250 .mu.m, and a water content of 30 to 50%
w/w.
[0045] In some embodiments of the present disclosure, the polymeric
eye insert does not include an additional pharmaceutically active
agent. In other embodiments, the polymeric eye insert may include
one or more additional pharmaceutically active agents. In some
embodiments, the one or more pharmaceutically active agents may be
selected from the group of ocular lubricants, anti-redness
relievers such as alpha-2 adrenergic agonists such as brimonidine,
apraclonidine etc, sympathomimetic amines such as tetrahydrozoline,
naphazoline, TRPM8 agonists such as menthol, menthol analogs,
steroids and nonsteroidal anti-inflammatory agents to relieve
ocular pain and inflammation, antibiotics, anti-histamines such as
olopatadine, anti-virals, antibiotics and anti-bacterials for
infectious conjunctivitis, anti-muscarinics such as atropine and
derivatives thereof for myopia treatment, and glaucoma drug
delivery such as prostaglandin and prostaglandin analogs such as
travoprost, or therapeutically suitable combinations thereof.
[0046] Polymeric eye inserts according to embodiments of the
present disclosure may be made using various processing techniques,
including but not limited to, compression molding and solution
casting. Compression molding may be carried out at temperatures and
pressures that do not change the material or lead to significant
side reactions. For example, compression molding of partially
hydrated polysaccharides may use a compressional force of
approximately 5,000-12,000 pounds at approximately 200-300 degrees
Celsius for approximately 1-2 minutes. Solution or film casting may
be carried out using solvents and/or co-solvents that may provide
homogeneous films with little to no defects. The solvent may be
removed by air or vacuum drying, resulting in an insert material
that may be free from residual solvents. For example, a 1% (w/v)
aqueous solution of polymer (or blend) may be cast and then allowed
to evaporate. The film may then be cut with an oval-shaped punch of
desired size and geometry. While compression molding and
solution/film casting have been described, it should be appreciated
that other processing techniques may be used without departing from
the present disclosure.
[0047] In one embodiment, the film casting method used was found to
generate reproducible inserts and good structural integrity. In
this embodiment, distilled water was placed in a 1L Erlenmeyer
flask followed by the addition of the polymer (s). The flask was
placed in a sonicator and attached to an overhead mechanical
stirrer. The mixture was sonicated and stirred for 60 minutes at
30.degree. C. The speed of the mechanical stirrer was adjusted to
700 rpm and allowed to stir for 60 minutes. The stirring was
stopped and the plasticizer (PEG and/or PVP) was added to the
flask. This mixture was stirred for 30 minutes under sonication at
700 rpm at 30.degree. C. until a homogeneous, clear solution was
obtained. The mechanical stirring was then stopped and the
sonication was allowed to continue for an additional 30 minutes in
order to remove all bubbles. The Erlenmeyer flask was then removed
from the sonicator and left to sit at room temperature for 30
minutes. For the preparation of the films, a petri dish (150 mm
diameter.times.15 mm height) was filled with about 150 g.+-.2 g of
the stock solution. The stock solution was subjected to different
evaporation techniques evaluation. In a first experiment, a vacuum
oven at 50.degree. C. was used. The petri dishes were placed in the
oven and the oven was evacuated using a vacuum pump. After 30
hours, the films obtained were yellow in color and some of the
films exhibited curved surfaces. The experiments were repeated at
45.degree. C., 40.degree. C., and 35.degree. C., under the same
vacuum conditions. All of the experimental conditions above yielded
colored films or films with non-uniform weight distribution. It was
also observed that the higher the temperature, the darker and more
intense the yellow color became. A preferred evaporation technique
included evaporation in a chamber equipped with a variable-speed
exhaust at room temperature. The airflow, temperature, and humidity
were all measured during the evaporation process. The technique
described above produced uniform evaporation and films with
consistent thickness.
[0048] As previously discussed, in vivo studies indicate that
traditional topical ophthalmic lubricants do not remain in the eye
longer than approximately 25 minutes. However, use of one or more
polymers combined with a plasticizer/softener, such as HP guar and
hyaluronic acid blended with a plasticizer (such as PEG), may
provide flexible films with tunable hydration and dissolution rates
for comfortable insertion. While certain embodiments of the present
invention are polymeric eye inserts containing a blend of
hyaluronic acid, HP guar and PEG, it should be appreciated that
other blends may be employed for polymeric eye inserts according to
other embodiments of the present disclosure. FIG. 1 depicts
placement of an eye insert according to an embodiment of the
present invention on the surface of the eye.
[0049] The eye inserts of the present disclosure are a platform to
deliver lubricants and other pharmaceutically active agents to
treat ocular surface symptoms (such as redness, itching and
dryness). In some embodiments, the polymeric eye inserts can be
used to prolong exposure of pharmaceutically active agents or
provide extended drug delivery of pharmaceutically active agents to
the eye. Thus, in some embodiments, the present disclosure provides
a method of providing extended drug delivery or prolonging exposure
of a pharmaceutically active agent to the eye, by administering a
polymeric eye insert including the pharmaceutically active agent to
a patient in need thereof.
[0050] In some embodiments, the present disclosure provides a
method of treating or reducing the signs and/or symptoms of dry eye
disease (keratoconjunctivitis sicca), comprising administering a
polymeric eye insert according to the present disclosure to a
patient in need thereof.
[0051] The following non-limiting Examples are provided to
illustrate embodiments of the invention.
EXAMPLES
Example 1
[0052] In an embodiment of the present disclosure,
hyaluronate-fluorescein (Creative PegWorks; Chapel Hill, N.C.),
sodium hyaluronate (Novozyme; Franklinton, N.C.), HP guar, HP
guar-fluorescein, PEG 400, and water may be used to form a
polymeric eye insert comprising HP guar and sodium hyaluronate;
however, it should be appreciated that more or fewer components
from different lots and/or distributors may be used to form a
polymeric eye insert without departing from the present
disclosure.
[0053] In order to form this HP guar/sodium hyaluronate insert,
approximately 100 mL of water was added to an Erlenmeyer flask that
had been autoclaved for approximately 30 minutes. The water was at
a temperature of approximately 22 degrees Celsius. The HA component
was tagged with fluorescein isothiocyanate (FITC) for tracking in
vivo release. FITC-hyaluronic acid (approximately 102.2 mg) was
then added to the water while stirring at approximately 23 degrees
Celsius at a setting of 500 (1/min) using an IKA.RTM. Ret
Control-Visc C hotplate/stirrer. Sodium hyaluronate (approximately
354.3 mg) was then added followed by HP guar (454.1 mg) and PEG 400
(approximately 97.2 mg). Additional water (approximately 100 mL)
was then added. The mixture was stirred for approximately 20 hours
at ambient temperature (approximately 22 degrees Celsius) using a
stirring setting of 600 (1/min). The solution was then poured into
a sterile polystyrene disposable petri dish (VWR, diameter of 55
mm, height of 15 mm). The petri dish containing the solution was
then placed in a Lindberg Blue M convection oven (Thermo
Scientific), heated at approximately 35 degrees Celsius, and then
dried under high vacuum at approximately 23 degrees Celsius for
approximately 1-2 days.
[0054] The resulting composition for this embodiment of a polymeric
eye insert was as follows: 102.2 mg (approximately 10%)
FITC-hyaluronic acid/354.3 mg (approximately 35%) sodium
hyaluronate, 454.1 mg (approximately 45%) HP guar, and 97.2 mg
(approximately 9%) PEG 400. Discs having a diameter of 6 mm were
then punched out for in vivo assessment studies. While a
methodology for forming an HP guar/hyaluronic acid insert according
to an embodiment of the present disclosure has been described, it
should be appreciated that other methodologies may be employed to
form these or similar polymeric eye inserts without departing from
the present disclosure.
[0055] An in vivo tolerability study was performed using single
polymeric eye inserts and New Zealand white rabbits. The polymeric
eye inserts utilized in this study were composed of 3-7 mm discs
containing an HP guar/hyaluronic acid blend using PEG as a
plasticizer. The hyaluronic acid component was tagged with
fluorescein isothiocyanate (FITC) for tracking in vivo release.
This study revealed acceptable tolerability and comfort using a 200
.mu.m thick film with a diameter of 6 mm. An in vivo retention
study also was performed using a single film of HP guar/hyaluronic
acid/PEG blend (using 5% FITC-hyaluronic acid). The film hydrated
in the cul-de-sac of the eye but fragments remained after two
hours. However, these fragments may be explained through low
frequency and intermittent blinking associated with the rabbit
subjects. Results from measuring fluorescence of these polymeric
eye inserts are shown in TABLE 1:
TABLE-US-00001 TABLE 1 FLUORESCENCE OF THIN FILM INSERTS-TIME
POINTS WITH .gtoreq.1.5X BASELINE LEVEL Minutes Post-Dose Film
Sample 2 10 20 30 45 60 90 120 Film #1 X X X X X X Film #2 X X X X
X Film #3 X X
[0056] All of the polymeric eye inserts were very well tolerated
with no physical reactions, discharge, squinting, or pawing. Once
placed, the insert remained in the eye with very little movement
until dissolved. Inserts dissolved during the first 30 minutes
after insertion. After one hour, lubricant residue was visible on
the corneal surface. After 6 hours, residue was no longer present.
It was determined that the 6-mm size was the largest diameter that
would fit in the cul-de-sac without infringement over the
corneal-scleral limbus. At 7 mm in diameter, the insert crossed the
limbus. However, other diameters of inserts may be employed without
departing from the present disclosure.
[0057] Tests to study polymeric eye inserts according to
embodiments of the present disclosure have been performed using a
Spectralis HRA-OCT. This is a diagnostic device that integrates
[0058] SD-OCT with the cSLO fundus imaging. The Anterior Segment
Module provided through the Spectralis may allow for imaging of
anterior segment structures. SD-OCT imaging is desirable because it
does not require a tagged test article, it offers both visual and
quantitative properties, it provides direct micrometer measurement
of the tear film/polymeric eye insert, and it allows for
acquisition of tear film height from four quadrants of the eye in
seconds.
[0059] Through this image, pooling of the polymeric insert in the
lower tear meniscus can be viewed.
Example 2
[0060] A variety of polymer inserts were prepared by film casting
in order to assess the compatibility of the polymers to make clear
and/or reasonably transparent insert films. The following polymer
formulations were prepared and evaluated using various
concentration ratios of each specified polymer: HA/PEG, HA/PVP/PEG,
HA/PVP, HA/HP-Guar/PEG, HP-Guar/PVP/PEG, HA/HP-Guar/PVP/PEG,
HA/HP-Guar/PAA/PEG, HA/HP-Guar/HPMC/PEG. A description of the
characterization methods of the insert films is provided below.
1. Morphology
[0061] The surface morphology of the insert films was tested using
the appropriate microscope. The texture and the transparency of the
insert films were investigated and the observations were recorded.
If the film surface was found to be clear and transparent it was
noted. If undissolved particulate or haziness were observed this
was also noted.
2. Thickness Uniformity
[0062] Four films were sampled and their thicknesses were evaluated
by cutting insert disks with 6 mm diameters. The thicknesses of the
disks were measured. The positions of the disk cutting were
selected randomly, in the middle and near the edges of each film.
The disks thicknesses were measured using a Mitutoyo digital
caliper. The mean and the standard deviation of 12 disks were
calculated for each film.
3. Weight Uniformity
[0063] In order to determine the weight uniformity, four different
films were selected and 12 disks with 6 mm diameters were cut. The
positions of the disks cut were selected randomly on the original
films. The weight of each disk was determined using a high accuracy
Sartorius balance. The weight of each individual disk was measured
and the average weight of 12 disks was determined for each film.
The standard deviation for the 12 data points was calculated and
recorded.
4. Percentage Moisture Absorption
[0064] For the percentage moisture absorption test, four circular
films with 150 mm diameters were prepared. From each film, four
circular disks with 20 mm diameters were cut. The four disks were
placed inside a chamber containing a 100 ml saturated solution of
aluminum chloride. The chamber was closed tightly for 72 hours.
During this time, the disk surface appearance stayed clear. The
disks were carefully removed from the chamber and the weight of
each disk was measured. The percentage moisture absorption of each
disk was calculated according to the following formula:
% MA=((Final weight-initial weight)/initial weight).times.100
[0065] The average percentage moisture absorption for 12 disks cut
from four different films was recorded.
5. Percentage Moisture Loss
[0066] The same films produced for percentage moisture absorption
were used for the percentage moisture loss measurements. Four disks
above were placed in a desiccator containing anhydrous calcium
chloride for 72 hours. The disks were then removed from the
desiccator and their weights were determined. The percentage
moisture loss for each film was calculated using the equation
below:
% ML=((initial weight-final weight)/final weight).times.100
[0067] The average moisture loss for the 12 disks cut from four
different films was recorded.
6. Folding Endurance
[0068] Four large, circular films with diameters of 150 mm were
prepared. Four square films with 4 cm.times.4 cm dimensions were
prepared from each film. The film strips were repeatedly folded at
the same place until the films broke or visibly cracked. The number
of times the films could be folded at the same place without
breaking gave the value of folding endurance. The data was
collected and the average results were recorded. The average
folding endurance of 16 square strips cut from the four different
films was determined.
7. Dissolution Time and pH of the Solution
[0069] Four circular disks with 6 mm diameters were cut from the
main circular films with 150 mm diameters. The films were placed in
a vial with 2 ml of DI water and the time required for complete
dissolution was recorded. The average dissolution time and the
standard deviation for each group were recorded.
8. Tensile Strength, Modulus, Displacement, and Percent
Elongation
[0070] Four film strips with 4 cm.times.2 cm dimensions were used
for each data point measurement. All films were inspected for air
bubbles and physical imperfections. The film strips were held
between two clamps positioned at 3 cm distances during the
measurement. The cell load used was 5 Kilograms. The strips were
pulled by the top clamp at a rate of 10 cm/min. The average tensile
strength, modulus, and percent elongation were measured and
reported.
[0071] Formulations used to prepare test films are provided below
with the polymer compositions and testing data. The TABLE 2 results
indicate that the presence of 5% PVP in the HA/PEG formulation
improved the flexibility and elasticity of the film. As shown in
TABLE 3, the presence of 30% PVP and 30% HP guar also provided a
film of relatively good elasticity and flexibility. The presence of
carbopol in the tested formulations resulted in brittle films as
shown by the data in TABLE 4. 200 ppm of menthol led to faster
dissolution rates and produced stiff films as shown in TABLE 5. The
films with <200 ppm menthol (such as 150 ppm) were improved with
similar modulus and % elongation to same films without menthol
added.
TABLE-US-00002 TABLE 2 HA/PVP AND PEG COMBINATIONS Tear Dissolution
Surface Modulus strength % Formulation time (min) pH (MPa) (MPa)
elongation Description HA 19 7.22 151.33 4.04 11.67 Films are
clear, (45.4%): (.+-.15) (.+-.0.49) (.+-.2.19) transparent, PVP
uniform, and (45.4%): bendable PEG (9.2%) HA (65%): 26.5 7.25 155
5.51 15.63 Films are clear, PVP (25%): (.+-.19.5) (.+-.0.69)
(.+-.0.6) transparent, PEG (10%) uniform, and bendable HA (85%):
27.4 7.3 159 4.7 21.04 Films are clear, PVP (5%): (.+-.9.8)
(.+-.0.28) (.+-.5.6) transparent, PEG (10%) uniform, and bendable
HA (90%): 30 7.2 190 6.4 13.5 Films are clear, PVP (10%) (.+-.2.6)
(.+-.0.39) (.+-.4.9) transparent, uniform, and bendable
TABLE-US-00003 TABLE 3 HA/HP-GUAR/PVP/PEG COMBINATIONS Tear
Dissolution time Surface Modulus strength % Formulation (min) pH
(MPa) (MPa) elongation Description HA (22.5%): 14 7.32 110 .+-.
9.24 3.59 .+-. 0.42 33.85 .+-. 9.8 Semi- HP- transparent Guar
(22.5%): to opaque PVP (45%): films PEG (10%) HA (30%): 33 7.21 147
.+-. 3.61 5.33 .+-. 0.5 38.75 .+-. 9.0 Semi- HP- transparent Guar
(30%): to opaque PVP (30%): films PEG (10%) HA (40%): 37 7.2 174
.+-. 18 7.15 .+-. 0.45 19.38 .+-. 6.03 Semi- HPguar (40%):
transparent PVP (10%): to opaque PEG (10%) films HA (42.5%): 53
7.23 160 .+-. 18 5.66 .+-. 0.75 18.33 .+-. 3.21 Semi- HP-
transparent Guar (42.5%): to opaque PVP (5%): films PEG (10% HA
(45%): 52 7.2 258 .+-. 42 8.99 .+-. 1.25 20.42 .+-. 3.15 Semi- HP-
transparent Guar (45%): to opaque PVP (10%) films
TABLE-US-00004 TABLE 4 HA/HP-GUAR/PAA/PEG COMBINATION Dissolution
Surface time (min) pH Tear (not (not Modulus strength % Formulation
measured) measured) (MPa) (MPa) elongation Description HA (22.5%):
229 .+-. 13.3 2.7 6.46 Stiff films HP- Guar (22.5%): PAA (45%): PEG
(10% HA (30%): 252 .+-. 13.89 4.41 7.29 Stiff films HP-Guar (30%):
PAA (30%): PEG (10%) HA (40%): 273 .+-. 9.71 6.82 6.5 Stiff films
HP-Guar (40%): PAA (10%): PEG (10%) HA (42.5%): 218 .+-. 10 7.2
10.00 Stiff films HP- Guar (42.5%): PAA (5%): PEG (10%) HA (45%):
190 .+-. 3.61 9.19 18.13 Stiff Films HP-Guar (45%): PAA (10%)
TABLE-US-00005 TABLE 5 HA/HP GUAR/PEG COMBINATION WITH 200 PPM
MENTHOL Tear Dissolution Surface Modulus strength % Formulation
time (min) pH (MPa) (MPa) elongation Description HA (45.4%): 66
7.15 189.35 10.56 16.67 The films HP-Guar (45.4%): are PEG (9.2%)
transparent HA (45.4%): 20 7.19 248.32 7.63 11.46 The films HP-Guar
(45.4%): are opaque PEG (9.2%): in the Menthol (200 ppm) presence
of menthol HA (45.4%): 47 7.15 187.67 7.99 18.13 The films HP-Guar
(45.4%): are opaque PEG (9.2%): in the Menthol (100 ppm) presence
of menthol
[0072] HA/HP Guar/PEG Film Characterization
[0073] Based on the data generated for the wide range of film
compositions it was determined that a preferred polymer composition
contained 45.4% hyaluronic acid (HA): 45.4% hydroxypropyl guar (HP
guar): 9.2% polyethylene glycol (PEG 400) (referred to as
[0074] Formulation 2 below). This film was prepared as follows:
TABLE-US-00006 TABLE 6 HA/HP GUAR/PEG COMBINATION Formulation 2
Film Composition Plasticizer Hyaluronic Hydroxypropyl Polyethylene
Solvent Media acid guar glycol Distilled water 5.107 grams 5.107
grams 1.035 grams 750 ml
[0075] In a 1L Erlenmeyer flask, 750 ml of distilled water was
poured into the flask followed by the addition of Hyaluronic Acid
(5.107 grams). The flask was then placed into the sonicator and
attached to an overhead mechanical stirrer. The mixture was allowed
to stir and sonicate 30 minutes (.+-.10 minutes) at a speed of 700
rpm at 25.degree. C. to 35.degree. C. until a homogeneous, clear
solution was obtained. Hydroxypropyl guar (5.107 grams) was then
added to the flask. The flask was placed back into the sonicator
and attached to an overhead mechanical stirrer. The mixture was
stirred and sonicated for 120 minutes (.+-.10 minutes) at a speed
of 700 rpm at 38.degree. C. to 42.degree. C. until a homogeneous,
clear solution was obtained. The plasticizer, polyethylene
glycol-400 (1.035 grams), was added into the flask. The mixture was
allowed to stir and sonicate for 30 minutes (.+-.10 minutes) at a
speed of 700 rpm at 40.degree. C. to 45.degree. C. until a
homogeneous, clear solution was obtained. The mixture was sonicated
without stirring for an additional 30 minutes (.+-.10 minutes) at
40.degree. C. to 45.degree. C. until a homogeneous, clear solution
(no bubbles) was obtained. The flask was allowed to stand at room
temperature for 30 minutes (.+-.10 minutes). After proper mixing,
the casting solution (150 g.+-.2 g) was poured into a clean petri
dish (150 mm.times.15 mm). The petri dish was dried at room
temperature for 60 h (.+-.5 h) in an evaporation chamber equipped
with an exhaust fan. After drying, the disk was cut into 9
cm.times.9 cm pieces and kept in an airtight bag for 24 h (.+-.3 h)
under controlled humidity (<50%) and temperature (23.degree. C.
to 26.degree. C.) levels for use in further characterization
studies.
TABLE-US-00007 TABLE 7 FORMULATION 2 AVERAGE WEIGHT MEASUREMENTS
Weight uniformity Formulation-2 (mean .+-. SD) mg F-2-50-2 4.425
.+-. 0.263 F-2-50-3 4.258 .+-. 0.188 F-2-50-4 4.492 .+-. 0.156
F-2-50-5 4.575 .+-. 0.280
TABLE-US-00008 TABLE 8 FORMULATION 2 MOISTURE ABSORPTION
MEASUREMENTS % Moisture Absorption Formulation-2 (mean .+-. SD)
F-2-50-2 5.052 .+-. 0.211 F-2-50-3 5.550 .+-. 0.289 F-2-50-4 4.770
.+-. 0.327 F-2-50-5 4.845 .+-. 0.606
TABLE-US-00009 TABLE 9 FORMULATION 2 MOISTURE LOSS MEASUREMENTS %
Moisture loss Formulation-2 (mean .+-. SD) F-2-50-2 8.630 .+-.
0.433 F-2-50-3 9.010 .+-. 0.608 F-2-50-4 9.148 .+-. 0.515 F-2-50-5
8.415 .+-. 0.323
TABLE-US-00010 TABLE 10 FORMULATION 2 FOLDING ENDURANCE
MEASUREMENTS Folding endurance Formulation-2 (mean .+-. SD)
F-2-50-2 38.50 .+-. 4.950 F-2-50-3 42.50 .+-. 6.363 F-2-50-4 37.50
.+-. 3.535 F-2-50-5 36.50 .+-. 6.369
TABLE-US-00011 TABLE 11 FORMULATION 2 DISSOLUTION TIME AND PH
MEASUREMENTS Dissolution time (min*) pH Formulation-2 Mean SD Mean
SD F-2-50-2 17 16.25 0.957 7.19 7.023 0.210 F-2-50-3 17 7.16
F-2-50-4 16 7.01 F-2-50-5 15 6.73
TABLE-US-00012 TABLE 12 FORMULATION 2 TENSILE STRENGTH, MODULUS,
AND PERCENT ELONGATION MEASUREMENTS Tensile strength Modulus
Displacement % (N/cm2) (N/cm2) (from 3 cm) Elongation Formulation-2
9.8 9.9 4.1 36.66 10.10 9.9 3.9 30 9.90 10.3 3.9 30 10.10 10.2 4.2
40 Mean 9.975 10.075 4.025 34.17 SD 0.15 0.206 0.150 5.0
Example 3
[0076] Direct thickness measurement of the tear film is possible
using HRA-OCT. HRA-OCT imaging was used to provide a measurement of
the tear film thickness following insertion of the insert and this
indirectly indicates the effect resulting from the delivery of
lubricant (i.e., enhancement of the tear film thickness indicates
delivery of lubricant and/or drug). Following insertion the insert
is expected to slowly dissolve and release lubricant and/or drug.
The general method used is described below using New Zealand
rabbits. In this procedure, an insert using 45.4% Hydroxypropyl
guar (HP guar) and 9.2% Polyethylene glycol (PEG 400) was evaluated
in rabbits using HRA-OCT. On Day 1, a single insert was placed into
the central, lower cul-de-sac of the right eye with forceps or
another appropriate device. Treatment was repeated on Day 3 with
inserts applied to the left eye. The study treatment design is
summarized in TABLE 13.
TABLE-US-00013 TABLE 13 EXAMPLE STUDY DESIGN Group Animal
Observation No. No. Treatment* Dosing Regimen Period 1 3 TA1 One
(1) insert on Day 3 after the last 2 3 TA2 Day 1 in the right
ophthalmic 3 3 TA3 eye. evaluation One (1) insert on Day 3 in the
left eye
[0077] Animals undergo optical coherence tomography (OCT) scans at
various time points up to 3 hours if needed. The method for OCT
imaging and image analysis in the rabbit is as follows: [0078] 1.
Lighting was dimmed in the imaging room to facilitate imaging.
[0079] 2. Lightly brush below the eye to be imaged with a
cotton-tipped applicator to induce a natural blink response. [0080]
3. Capture one horizontal image centered at the apex of the cornea.
[0081] 4. Lightly brush below the eye again with a cotton-tipped
applicator to induce a natural blink response. [0082] 5. Capture
one vertical image centered at the apex of the cornea. [0083] 6.
Document dose information and image numbers. [0084] 7. Determine 3
points on each image for analysis (horizontal: nasal, apex,
temporal region of the eye; vertical: top, apex, bottom of the
eye). [0085] 8. Use the measurement tool on the Bioptogen to
determine tear film thickness at each analysis point and document
measurements.
[0086] Treatment groups and imaging schedules for the test animals
are presented below in TABLES 14 and 15.
TABLE-US-00014 TABLE 14 TREATMENT GROUPS Hydration Drop No. of
Group No. Treatment (BSS) Animals 1 BSS 30 uL dose every 15 4
minutes 2 45.42% Sodium- 30 uL dose every 15 4 HA/45.42% HP-
minutes Guar/9.16% PEG400 Insert 3 45.42% Sodium- 30 uL dose at 4
HA/45.42% HP- insertion Guar/9.16% PEG400 Insert 4 Lacrisert N/A
4
TABLE-US-00015 TABLE 15 GROUP IMAGING SCHEDULE Group Imaging
Schedule 1 Pre-dose Immediately Post-Dose 15 and 30 Min Post
l.sup.st Dose 2 Pre-dose Immediately Post-Dose 15, 30, 45, 60, 75
& 90 Min Post-Dose 3 Pre-dose Immediately Post-Dose 15, 30, 45,
60, 75, 90, 105, 120, 135 & 150 Min Post-Dose 4 Pre-dose
Immediately Post-Dose 15, 30, 45, 60, 75, 90, 105, 180 & 360
Min Post-Dose
[0087] FIG. 9 presents the tear film thickness data from the
testing. In this test LACRISERT.RTM. was used as a control. In this
in vivo experiment there were no significant issues associated with
safety or tolerability with LACRISERT.RTM. and the test articles
containing HPGuar/HA/PEG. In this in vivo test the test articles
were exposed to two different post-dosing regimens. In one case
following insertion the BSS was added every 15 min to try and
accelerate the dissolving insert. In the second case BSS was dosed
once following the insert insertion. The LACRISERT.RTM. was simply
inserted as per instructions for the human eye. The OCT
measurements showed an increase in tear film thickness for the test
articles for both scenarios. The BSS addition accelerated the
dissolving insert as showed by the rapid increase in tear film
thickness around 5 min to a max tear film thickness of 50 microns
after 15 min. Comparatively, the scenario with a single post
insertion drop showed the tear film thickness to extend across 90
min followed by decrease to baseline within 2 hours. The
LACRISERT.RTM. during this time frame showed no noticeable effects
on the tear film thickness and following 3 hours it remained in a
solid-like state. The HA/HPG/PEG insert test articles were
completely dissolved after 2 hours in this experiment.
Example 4
Inserts With Pharmaceutically Active Agents
[0088] The inserts of the present invention may include one or more
pharmaceutically active agents, as detailed supra. An insert film
prepared with an anti-muscarinic, atropine, is provided below.
Eye Insert Preparation With Atropine
[0089] 40% Hyaluronic acid (HA): 40% hydroxypropyl guar (HP): 10%
Polyethylene glycol (PEG 400): 10% Polyvinyl pyrrolidone: 500 ppm
Atropine
TABLE-US-00016 TABLE 17 ATROPINE INSERT FORMULATION Film
formulation Plasticizer Solvent Hydroxy- Polyvinyl Polyethylene
Drug Media Hyaluronic propyl pyrrolidone glycol Atropine Distilled
acid guar (Aldrich) (Aldrich) (Aldrich) water 2.1 g 2.1 g 0.525 g
0.525 gm 0.175 g 350 ml
Procedure:
[0090] To prepare 350 g of the insert formulation the following
quantities are needed: HA (2.1 g): HP-guar (2.1 g): PEG-400 (0.525
g): PVP (0.525 g): Atropine (0.175 g) in 350 ml distilled water. In
1L Erlenmeyer flask, 350 ml distilled water was mixed with 2.1 g
Hyaluronic acid and 0.525 g polyvinyl pyrrolidone. The flask was
attached to an overhead mechanical stirrer and the mixture was
stirred at 600 RPM for 30 minutes at 35.degree. C. Then 2.1 g
Hydroxypropyl guar was added. The mixture was then stirred for 120
minutes at 38.degree. C. until a homogeneous clear solution is
obtained. The plasticizer polyethylene glycol-400 (0.525 g) and
Atropine (0.175 g) were then added into the flask and the mixture
was stirred for another 30 minutes at 700 RPM. The mixture was left
to cool down for 30 minutes. At this stage the solution was ready
for film casting.
Film Casting:
[0091] 150 g.+-.2 g of the solution was poured into clean petri
dish (150 mm.times.15 mm). The petri dish was dried for 30 h at
room temperature for 30 h using a drying chamber. The obtained film
was clear and did not show any crystallization or unusual visual
appearance.
Eye Insert Preparation With Povidone Iodine
[0092] In another example, a broad spectrum biocide povidone iodine
was utilized with the insert. This insert had the following
formulation: 40% Hyaluronic acid (HA): 40% hydroxypropyl guar (HP):
10% Polyethylene glycol (PEG 400): 10% Polyvinyl pyrrolidone and
500 ppm PVP-I in the total mass.
Procedure:
[0093] Procedure for preparing 350 g batch of the formulation in 1L
Erlenmeyer flask with concentration 0.015 g/mL. HA (2.1 g): HP-guar
(2.1 g): PEG-400 (0.525 g): PVP (0.525 g): PVP-I (0.175 g) in 350
ml distilled water. In 1L Erlenmeyer flask, 350 mL distilled water,
Hyaluronic acid (2.1 g) and polyvinyl pyrrolidone (0.525 g) was
added. The flask was placed into the sonication bath and attached
to overhead mechanical stirrer. The mixture was stirred and
sonicated at the same time for 30 minutes (.+-.10 minute) at a
speed of 600 RPM and at a temperature between 25.degree. C. to
35.degree. C. until a homogeneous clear solution was obtained. The
Hydroxypropyl guar (2.1 g) was then added. The flask content was
stirred for 120 minutes (.+-.10 minute) at a speed of 600 RPM and
at a temperature between 38.degree. C. to 41.degree. C. until a
homogeneous clear solution was obtained. The polyethylene
glycol-400 (0.525 g) and PVP-I (0.175 g) were then added into the
flask. The mixture was stirred for extra 45 minutes. 150 gm 2 g of
the solution was poured in a clean petri dish (150mm.times.15mm).
The petri dish was dried at room temperature for 30 h (.+-.1 h) in
a ventilated chamber. 500 ppm of PVP-I was calculated based on the
total mass including water.
Example 5
[0094] Tear film measurements for polymeric eye inserts according
to embodiments of the present disclosure were also compared to tear
film measurements of SYSTANE.RTM. ULTRA eye drops as well as
GENTEAL.RTM. gel eye drops and PROVISC.RTM. injectable.
[0095] FIGS. 2A-2C depict tear film measurements for the
SYSTANE.RTM. ULTRA eye drops pre-dose (FIG. 2A), immediately
post-dose (FIG. 2B) and 5 minutes post-dose (FIG. 2C). FIGS. 2A-2C
reflect that the tear film measures 22 .mu.m pre-dose, 60 .mu.m
immediately post-dose, and 19 .mu.m 5 minutes post-dose.
[0096] FIGS. 3A-3C depict tear film measurements for the
GENTEAL.RTM. gel eye drops pre-dose (FIG. 3A), immediately
post-dose (FIG. 3B) and 5 minutes post-dose (FIG. 3C). FIGS. 3A-3C
reflect that the tear film measures 20 .mu.m pre-dose, 31 .mu.m
immediately post-dose, and 19 .mu.m 5 minutes post-dose.
[0097] FIGS. 4A-4E depict tear film measurements for the
PROVISC.RTM. injectable pre-dose (FIG. 4A), immediately post-dose
(FIG. 4B), 5 minutes post-dose (FIG. 4C), 10 minutes post-dose
(FIG. 4D) and 20 minutes post-dose (FIG. 4E). FIGS. 4A-4E reflect
that the tear film measures 19 .mu.m at pre-dose, 194 .mu.m
immediately post-dose, 114 .mu.m at 5 minutes post-dose, 61 .mu.m
at 10 minutes post-dose, and 16 .mu.m at 20 minutes post-dose.
[0098] Each of the tear film measurements set forth in FIGS. 2A-2C,
3A-3C, and 4A-4E reflect the tear film increases in thickness
immediately post-dose but returns to a thickness similar to that
measured pre-dose within anywhere from 5 to 20 minutes
post-dose.
[0099] In contrast, FIGS. 5A-5I reflect tear film measurements
associated with insertion of a polymeric eye insert according to
embodiments of the present disclosure. These measurements reflect
that the tear film measures 14 .mu.m pre-dose (FIG. 5A), 20 .mu.m
15 minutes post-dose (FIG. 5B), 81 .mu.m 30 minutes post-dose (FIG.
5C), 45 .mu.m 45 minutes post-dose (FIG. 5D), 43 .mu.m 1 hour
post-dose (FIG. 5E), 37 .mu.m 1 hour and 15 minutes post-dose (FIG.
5F), 33 .mu.m 1 hour and 30 minutes post-dose (FIG. 5G), 22 .mu.m 1
hour and 45 minutes post-dose (FIG. 5H), and 18 .mu.m 2 hours
post-dose (FIG. 51). Accordingly, in this embodiment of the present
disclosure, the tear film thickness does not return to its pre-dose
thickness until approximately 2 hours post-dose.
[0100] Additional tear film measurements were performed on New
Zealand white rabbits. Each rabbit received a single polymeric eye
insert. 3 horizontal and 3 vertical images were obtained per time
point. Three points on each line were measured and zoomed in to
800% to determine the depth of the tear film/test article.
[0101] FIG. 6A reflects mean tear film measurements using polymeric
eye inserts according to embodiments of the present disclosure.
Three rabbits were tested, and each rabbit blinked three times
prior to image capture. The insert diameter (6 mm) remained the
same across testing of each rabbit, and the insert weight ranged
from 2.6 mg to 2.9 mg. FIG. 6B reflects tear film measurements by
individual animal. FIG. 6C reflects tear film measurements based on
location in the eye including bottom of the eye, top of the eye,
temporal and nasal measurements.
[0102] Further testing on New Zealand white rabbits measured the
dynamic change of tear film thickness associated with polymeric eye
inserts according to embodiments of the present disclosure (FIG.
7A). The insert diameter remained at 6 mm. The insert weight for
oculus sinister (OS) ranged from 3.2 to 3.8 mg, and the insert
weight for oculus dextrus ranged from 2.2 to 2.6 mm. FIG. 7B
reflects tear film measurements by location (apex, nasal, temporal,
top, and bottom).
[0103] This testing also made similar measurements with respect to
GENTEAL.RTM. gel at a dosage of 80 .mu.L or approximately 76.3 mg
into the central lower cul-de-sac of the eye. FIG. 8 reflects mean
GENTEAL.RTM. gel tear film measurements for the right and left
eye.
[0104] After taking measurements for both the polymeric eye insert
according to embodiments of the present disclosure and GENTEAL.RTM.
gel, the results were analyzed. TABLE 18 below reflects the number
of animals with a mean of 6 readings greater than or equal to 30
.mu.m.
TABLE-US-00017 TABLE 18 Test Minutes Post Dose Article 15 30 45 60
75 90 105 120 135 Genteal 1 0 0 0 0 0 0 0 0 Gel (microns) Eye 3 6 7
5 2 1 0 1 1 Insert (microns)
[0105] This testing confirmed that tear film thickness change can
be effectively monitored through Spectralis HRA+OCT. Inserts begin
to dissolve by 15 minutes post-dose in most animals. Most animals
dosed with a polymeric eye insert according to embodiments of the
present disclosure had a significant increase of tear film
thickness for at least 30 minutes post-dose. It should be
appreciated that the location of the polymeric eye insert, both
initial placement and movement after blinking, may create
variations in data, particularly in early time points; however, IR
image and OCT can help to differentiate the influence of insert
location. It also should be appreciated that the weight of the
insert may have an impact on length of retention. Further, it
should be appreciated that intrinsic differences among animals may
impact the results. For example, one animal had the longest
duration of increased tear film thickness regardless of insert
size; however, the larger insert retained approximately 45 minutes
longer. It also was noted that aqueous solutions caused little tear
film thickness changes.
[0106] As reflected through the studies described above, a
polymeric eye insert according to an embodiment of the present
disclosure may assume the form of a dissolvable film comprised of
hydrophilic polymers with high mucoadhesive and H-bonding
properties. The film may contain one or more naturally derived
polysaccharides or synthetic polymers that are biocompatible and
well-tolerated by the eye. The dissolvable film may have a thin
film design that may allow for easy, comfortable insertion into the
cul-de-sac of the eye, as the film should be small enough to fit
into the cul-de-sac with little-to-no irritation upon insertion but
large enough so that dissolution occurs over a longer period of
time. Such a dissolvable film may hydrate quickly to form a soluble
gel and release lubricant and/or a pharmaceutically active agent
within a short time frame (e.g., the first 5-10 minutes following
insertion). This slow pulsed flow of lubricant may maximize the
adhesion and residence time of the lubricant on the ocular surface
as compared to topical drop usage. The retention time of the
lubricant on the eye may be increased by slow delivery in the tear
film and ocular surface.
[0107] Insertion of a dissolvable film according to embodiments of
the present disclosure does not lead to visual disturbances after
several minutes. It should be appreciated that the dissolvable film
may retain a lubricant for approximately two hours or more;
however, there may be embodiments of the present disclosure where
retention may occur over approximately 30-60 minutes. Accordingly,
a dissolvable film or polymeric eye insert according to embodiments
of the present disclosure may provide advantages, including but not
limited to, quick dissolution for reduced blurring, a thin film
design for enhanced wetting kinetics and ocular tolerability,
improved comfort on insertion, and reduced foreign sensation.
Further, tolerability and delivery of lubricant may be improved as
compared to other topical delivery systems or inserts.
[0108] While embodiments of the present disclosure have been
described for use as lubricants and/or pharmaceutically active
agents to treat dry eye, it should be appreciated that polymeric
eye inserts according to embodiments of the present disclosure also
may have advantages for ophthalmic delivery of pharmaceutically
active agents to treat other ocular disorders. A non-exhaustive
list of such disorders includes ocular hypertension, glaucoma,
glaucomatous retinopathy, optic neuropathy, macular degeneration,
diabetic retinopathy, choroidal neovascularization, proliferative
vitreoretinopathy, ocular wounds and infections, and myopia.
[0109] While some embodiments have been described as films, it
should be appreciated that a polymeric eye insert according to
embodiments of the present disclosure can assume a variety of
shapes including, but not limited to, films, rods and spheres. In
an embodiment of the present disclosure, a circular film of
approximately 0.5 to 10 mm diameter may be employed. In other
embodiments, circular films of 4-7 mm diameter are particularly
preferred. Various other film shapes may be used in certain
embodiments, such as those presented in FIGS. 10A-10C.
[0110] Regardless which shape the insert assumes, a polymeric eye
insert according to embodiments of the present disclosure should be
small enough to fit into the cul-de-sac of the eye and be rapidly
wetted so that there is little or no irritation upon insertion. The
insert also should be large enough to allow for dissolution over
anywhere from approximately 30-120 minutes to allow for release of
the lubricant(s) and/or pharmaceutically active agents to occur.
The insert should also have a thickness that is relatively
comfortable for the user. A preferred thickness is between 50-250
microns, and a most preferred thickness is between 70-150 microns.
The target thickness is 90 microns for films dissolving in less
than 2 hours.
Example 6
Monkey Tolerability Study
[0111] The cynomolgus male monkey of Chinese origin (protein-naive)
was selected for this study based on the pharmacological and
anatomical relevance of the monkey eye and following tolerance
assessment in rabbit. The monkey eye blinks with similar frequency
to the human. Clinical observations were performed for tolerability
of the ocular test article at 15, 30, 45, 60, 120, 180, and 240
minutes post-dose. Special attention was afforded to tear film
retention and tolerability. Gross examinations include tearing,
redness, swelling, and blinking. At 24 hours post dose, animals in
Groups 1 and 2 are lightly sedated and the treated eye is
thoroughly examined for any presence of the tear film. If any tear
film is detected, it is noted in the clinical observations and the
remaining film removed. Additional clinical observations are noted
as necessary if abnormalities continue past the final observation
time point. If any unexpected clinical signs are present, the
veterinarian is notified immediately. Animals are restrained
manually, chemically (Ketamine or alternative e.g., Telazol, if
needed, per Veterinary Guidelines), or mechanically (chair). Dosing
is with light sedation. Observations are performed on lightly
sedated or awake animals. The test articles are administered to
lightly sedated animals (Ketamine 5-15 mg/kg, IM or alternative
[e.g., Telazol 5-10 mg/kg, IM]). The time of dose administration is
considered as the completion of dosing to the one eye. Once lightly
sedated, a single insert test article is placed into the central,
lower cul-de-sac of the left eye of all animals with forceps or
another appropriate device.
[0112] Eye insert disks are composed of 40% HPGuar/40% HA/10%
PVP/10% PEG and are labelled as TA1 and TA2. TA1 has a diameter of
6 mm and a thickness of 86 microns (std. deviation is 8.4 microns).
TA2 has a diameter of 6 mm and a thickness of 108 microns (std.
deviation is 8.3 microns). SYSTANE ULTRA.RTM. is used as the
control.
[0113] Observations and Conclusions
[0114] Following T=0 dosing, the thinner TA1 inserts were harder to
place and they tended to fold once they touched the moisture on the
tissue but once situated they lay flat without much trouble. The
thicker films, TA2, did not fold and were easy to insert and lay
flat immediately on the tissue. Both Groups TA1 and TA2 had mild to
moderate tearing after insertion (the animals that received the
drops had no tearing). There have been no signs of irritation, no
redness, no eye rubbing and no other squinting observed over three
hours. After 24 hours, no residual insert material was present in
any animal and all of the treated eyes looked acceptable compared
to the SYSTANE ULTRA.RTM. topical drop, with no redness, swelling
or any other signs of irritation.
Example 7
Human Study of a Lubricant Polymeric Eye Insert
[0115] In order to assess the biocompatibility, safety, and
tolerability of an polymeric eye insert, a study of an embodiment
of the present disclosure was tested in a randomized, cross-over
design in human participants. Over the course of one study day, a
total of three treatments were applied to each participant: 2
polymeric eye inserts and one ocular lubricant drop. Treatments
were applied to one eye only, with the fellow untreated eye acting
as the control eye.
[0116] Study Design:
[0117] Ten participants enrolled in the study (5 female, 5 male).
The mean age of the participants was 35.5 years (median 33 years,
ranging from 23 to 61 years).
[0118] The outcome measures for the study were as follows:
[0119] Primary outcome variable: Subjective rating of ocular
comfort.
[0120] Secondary outcome variable: Subjective rating of visual
blur, polymeric eye insert dissolution rate, Investigator rating of
handling and non-invasive tear break-up time (NITBUT).
[0121] The study was conducted as follows: The study day lasted
approximately 9 hours and included a screening and eligibility
check, insertion of the first treatment (polymeric eye insert or
ocular lubricant drop) into 1 eye, assessments, and eye rinse
approximately 2 hours after insertion. After waiting for a minimum
of 1 hour, the second treatment was applied to the other eye (eye
not previously used) and procedures repeated. There was a wait of a
minimum of 1 hour before the final treatment was applied and
procedures repeated. For each treatment, ocular comfort and vision
ratings were completed: prior to insertion, 5, 15, 30, 60, 90, and
105 minutes after insertion to assess tolerability of the
treatment. Tear film assessments were carried out 5, 60, 90 and 105
minutes after insertion. Ocular safety measurements were carried
out at screening and after each treatment. At the end of the study
day, participants were asked to indicate their treatment
preference.
[0122] Study Materials:
[0123] The two different polymeric eye inserts are as follows:
TABLE-US-00018 TABLE 19 polymeric eye insert 1 polymeric eye insert
2 (Thick insert) (Thin insert) Ingredients Hydroxypropyl Guar
Hydroxypropyl Guar (HPGuar) 40% (HPGuar) 40% Hyaluronic Acid (HA)
40% Hyaluronic Acid (HA) 40% Polyvinylpyrrolidone/
Polyvinylpyrrolidone/ Polyethylene Polyethylene Glycol Glycol
(PVP/PEG) 10% (PVP/PEG) 10% Other information UV sterilised UV
sterilised Diameter 6 mm circular shape 6 mm circular shape
Thickness 135-145 .mu.m 105-115 .mu.m
[0124] Ocular lubricating drops (Systane) were used as a control
treatment. The components of the ocular lubricating drops are as
follows:
TABLE-US-00019 Ingredients Hydroxypropy Guar (HPGuar), Polyethylene
Glycol (PEG) 400 0.4%, Propylene Glycol 0.3% Preservative and
disinfectant/ POLYQUAD (polyquaternium-1) cleaning agent 0.001%
w/v
[0125] This study took place over one study day. During the study
day, participants were asked to attend five scheduled visits.
[0126] Visit 1: Screening and eligibility (0.75 hrs)
[0127] Visit 2: Treatment 1 insertion, assessments and removal (2.0
hrs)
[0128] Visit 3: Treatment 2 insertion, assessments and removal (2.0
hrs)
[0129] Visit 4: Treatment 3 insertion, assessments and removal (2.0
hrs)
[0130] Visit 5: Study Exit (0.25 hrs).
[0131] A one-hour washout period was applied between visits 2 and
3, and between 3 and 4.
[0132] The procedures at each visit are summarized in Table 20
TABLE-US-00020 TABLE 20 Study visits and Procedures Screening &
Treatment insertion Measurement & Eligibility & assessment
Study Exit processes (0.75 hrs) (2 hrs/treatment) (0.25 hrs)
Informed Consent Demographics Medical history VA (logMAR) with
spectacles Full slit lamp biomicroscopy Partial slit lamp
biomicroscopy Confirm eligibility Treatment insertion Treatment
removal Subjective ratings (questionnaires) Investigator ratings
(ease of insertion) Tear film meniscus height Non-invasive tear
film break-up time with a placido disk device Assessment of
polymeric eye insert
[0133] Study Results:
[0134] Primary outcome variable--comfort rating
[0135] At each of the time points (prior to insertion, 5, 15, 30,
60, 90, and 105 minutes after insertion), participants were asked
the following question, "How would you rate the comfort of your
eyes?".
[0136] Participants responded using a 0 to 100 scale where 0
indicates "Very poor comfort" and 100 indicates "Excellent
comfort". The results are provided in FIG. 11.
[0137] As seen in FIG. 11, there was a statistically significant
difference between the inserts and the drop at the 5 and 15-minute
time points, with the drop having statistically significant higher
comfort ratings. The two inserts performed similarly in terms of
comfort ratings, however there was a statistically significant
difference at the 60-minute time point, with the comfort of the
thick insert rated higher (90 vs 95, p=0.04).
[0138] Secondary Outcome Variable
[0139] Results of the Secondary Outcome Variables Were as
Follows:
[0140] Visual blur--At each of the time points (prior to insertion,
5, 15, 30, 60, 90, and 105 minutes after insertion), participants
were asked the following question, "How would you rate the visual
blur of your eyes?". Participants responded using a 0 to 100 scale
where 0 indicates "Extremely blurry. Unable to see properly" and
100 indicates "Not blurry at all". The results are provided in FIG.
12.
[0141] As seen in FIG. 12, compared to the drops, both inserts
caused statistically significantly lower ratings of visual blur at
the 5, 15 and 30-minute time points (p<0.01 or p=0.01).
Additionally, the thick insert caused a statistically significant
lowering of visual blur ratings at the 60-minute time point (93 vs
100, p=0.01), however there was not a statistically significant
difference between the thick and thin insert at 60 minutes (88 vs
93, p=0.28).
[0142] Ease of insertion by clinicians--Investigators provided an
assessment of the ease of insertion of the polymeric eye inserts
during at insertion Ease of insertion was assessed using a 0 to 4
scale in 0.5 steps where 0 indicates "Very easy" and 4 indicates
"Very difficult".
[0143] Results are as follows: Thin insert--1.3 .+-.0.5, Thick
insert--1.6 .+-.0.5. The results show that there were no
statistically significant difference in the ease of insertion of
the two inserts. Further, Inserts were relatively easy to place in
eye even with minimal training.
[0144] polymeric eye insert dissolution rate--The degree of
dissolution of the polymeric eye inserts were assessed at each time
point. At each of the time points (at insertion, 45, 60, 75, 90,
and 105 minutes after insertion), Investigators provided an
assessment of the degree of dissolution of the polymeric eye
inserts. Dissolution grading was done using a 0 to 6 scale, where 0
indicates "No dissolution" and 6 indicates "completely
dissolved".
[0145] Results are shown in FIG. 13 and indicate that .about.90% of
the lubricant solid material is dissolved between 60-90 min.
Further, the data indicate that there were no statistically
significant differences in the dissolution grade of the two
inserts.
[0146] NITBUT--An assessment of the non-invasive tear breakup time
(NITBUT) was performed at insertion and 60 minutes, 90 minutes, and
105 minutes after insertion. Results are presented in FIG. 14.
[0147] FIG. 14 illustrates that there were statistically
significant differences between the treatment eye and the control
eye for both inserts at the insertion time point, with the NITBUT
of the treatment eye being larger than the control eye (thick
insert: 18.52 vs 8.12, p=0.01; thin insert:17.26 vs 7.93,
p<0.01). There were also statistically significant differences
with the thick insert between treatment and control eyes at the 60
and 90-minute time points (60 mins: 14.47 vs 5.89, p=0.02; 90 mins:
10.36 vs 5.77, p=0.02).
[0148] Tear meniscus--Investigators provided an assessment of tear
film meniscus height during the treatment at time points and 60
minutes, 90 minutes, and 105 minutes after insertion. Results are
presented in FIG. 15.
[0149] Other Variables
[0150] Ocular irritation--At each of the time points (prior to
insertion, 5, 15, 30, 60, 90, and 105 minutes after insertion),
participants were asked, "How would you rate the feeling of ocular
irritation of your eyes?" Participants responded using a 0 to 100
scale where 0 indicates "Intense feeling of ocular irritation" and
100 indicates "No feeling of ocular irritation at all".
[0151] Results are shown in FIG. 16. As seen in FIG. 16, There were
statistically significant differences between the treatment eye and
the control eye for both inserts at the 5-minute time point, with
the ocular irritation rating of the treatment eye being
statistically significantly lower (thick insert: 71 vs 100, p=0.01;
thin insert: 67 vs 99, p=0.02). There were no statistically
significant differences in ocular irritation rating between the two
inserts.
[0152] Ocular dryness--At each of the time points (prior to
insertion, 5, 15, 30, 60, 90, and 105 minutes after insertion),
participants were asked, "How would you rate the dryness of your
eyes?" Participants responded using a 0 to 100 scale where 0
indicates "Very dry" and 100 indicates "No dryness at all". Results
are shown in FIG. 17. There were no statistically significant
differences between the treatment and control eyes in terms of
dryness for any treatment. There were also no differences between
inserts.
[0153] Burning/stinging--At each of the time points (prior to
insertion, 5, 15, 30, 60, 90, and 105 minutes after insertion),
participants were asked, "How would you rate the burning/stinging
sensation of your eyes?" Participants responded using a 0 to 100
scale where 0 indicates "Intense feeling of burning/stinging" and
100 indicates "No burning/stinging at all". Results are presented
in FIG. 18. There were no statistically significant differences
between the treatment and control eyes in terms of burning/stinging
sensation for any treatment. There were also no differences between
inserts.
[0154] Itching--At each of the time points (prior to insertion, 5,
15, 30, 60, 90, and 105 minutes after insertion), participants were
asked, "How would you rate the feeling of itchiness of your eyes?"
Participants responded using a 0 to 100 scale where 0 indicates
"Intense itching" and 100 indicates "No itching at all". Results
are presented in FIG. 19. As seen in the results, there were no
statistically significant differences between the treatment and
control eyes in terms of itching for any treatment. There were also
no differences between inserts.
[0155] High illumination, high contrast visual
acuity--Investigators provided an assessment of high contrast, high
illumination visual acuity at screening and during the treatment
visits at insertion and 60 and 105 minutes after insertion. There
were statistically significant differences between treatment and
control eyes at the insertion and 60-minute time points, with
participants exhibiting a significant reduction in visual acuity.
(Insertion: thick insert: 0.05 vs -0.11, p<0.01; thin insert:
0.07 vs -0.10, p=0.01)(60mins: thick insert: -0.06 vs -0.1, p=0.03;
-0.07 vs -0.10, p=0.02). The difference in visual acuity at 60
minutes equates to approximately 2 letters, which may not be
considered clinically relevant. Visual acuity had returned to
normal by the end of the treatment visit. There were no
statistically significant differences in visual acuity between
inserts.
[0156] Ocular health--Bulbar and limbal hyperemia (redness) and
neovascularization were assessed using a 0-4 scale in 0.1 steps
(Efron Scale), with 0 indicating normal and 4 indicating severe.
There were no clinically relevant differences for any measure of
ocular health.
[0157] Summary of Results [0158] Primary clinical outcome of
subjective comfort and tolerability was achieved. The inserts were
tolerated by the participants and the ocular health for all
patients during and post-wear was not negatively affected. [0159]
There were no statistically significant differences between SYSTANE
ULTRA and the inserts for burning, stinging, itching or dryness in
the participants. [0160] Inserts did not negatively impact ocular
health. [0161] The in vivo rabbit and clinical comfort study data
suggest that the device could be a valuable platform for delivery
of ocular lubricants and other topical ocular drugs.
[0162] Although the present disclosure and its advantages have been
described in detail, it should be understood that various changes,
substitutions and alterations can be made herein without departing
from the spirit and scope of the disclosure as defined by the
appended claims. Moreover, the scope of the present application is
not intended to be limited to the particular embodiments of the
process, machine, manufacture, composition of matter, means,
methods and steps described in the specification. As one of
ordinary skill in the art will readily appreciate from the
disclosure, processes, machines, manufacture, compositions of
matter, means, methods, or steps, presently existing or later to be
developed that perform substantially the same function or achieve
substantially the same result as the corresponding embodiments
described herein may be utilized according to the present
disclosure. Accordingly, the appended claims are intended to
include within their scope such processes, machines, manufacture,
compositions of matter, means, methods, or steps. All of the
publications and patent applications and patents cited in this
specification are herein incorporated in their entirety by
reference.
* * * * *